Project Summary In recent decades, Central and South America have experienced spillover of endemic arthropod-borne viruses (arboviruses) from wildlife reservoirs into humans, exchange and recombination of emerging arboviruses within the region, resurgence of arboviruses previously controlled by vaccination or vector control, introduction and spread of novel arboviruses, and exportation of viruses to other regions. Furthermore, there is great concern that newly-introduced Zika virus may spill back into an enzootic transmission cycle in the Americas. Central and South America encompass enormous vertebrate and invertebrate biodiversity, and these species harbor a broad range of arboviruses whose risk of spillover and spread in humans is presently unknown. Increases in the rates of global travel, invasion of novel vector species, urban expansion, deforestation, and global climate change all elevate the risk of further arbovirus emergence, as does the breakdown of public health structures in Venezuela. The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE- NEO) project will provide a network of surveillance sites in the neotropics coupled to cutting-edge modeling approaches in order to anticipate and counter emerging arboviruses. Aim 1 will identify novel and known arboviruses as well as the host-vector networks that sustain transmission of these viruses within the neotropics, map the spatial distribution of these transmission networks, and characterize virus transmission dynamics within these networks. To do so, we will collect mosquitoes and other vectors as well as non-human primates and other vertebrate hosts at multiple sites in areas of high and varied biodiversity in Panama and Brazil and screen these samples for known and novel arboviruses. These data will then be analyzed using niche modeling, machine learning to predict undiscovered hosts and vectors, and dynamical transmission models. Aim 2 will focus on prospective and retrospective analysis of human infection and disease. To do so, we will leverage ongoing human clinical cohorts at multiple sites in Brazil and Panama. We will extend and expand these cohorts, with a particular focus on the immune-mediated interactions among multiple arboviruses at sites of hyperendemicity. We will also develop novel diagnostics to capture known and novel arboviruses and model the impact of human and non-human primate movement on spillover and spillback of target arboviruses. Data and models generated via these two aims will forewarn local, regional and global public health agencies of arboviruses within Central and South America that pose particularly high risk of spillover, emergence into transmission among humans, and/or international spread. Moreover CREATE-NEO will build local capacity to predict, detect and respond to emerging arboviruses at their point of origin, thereby maximizing the potential to avert full-blown emergence.